Several publications and patent documents are cited through the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated herein by reference as though set forth in full.
Pediatric arthritis is the leading cause of acquired disability in children, afflicting about one in 1000 children worldwide,1 all ethnicities and both genders, with onset as early as the first year of life. Classification schemes for pediatric arthritis are under evolution, akin to the recent classification changes for adult rheumatoid arthritis;2 juvenile rheumatoid arthritis (JRA) is the term used historically in North America, while juvenile idiopathic arthritis (JIA) is the preferred name elsewhere, and is now used increasingly worldwide. JIA is defined as a group of chronic arthritides of unknown etiology, occurring in children from 0 to 16 years of age.3 Morbidity associated with JIA can be life-long—with as many as 50% of children with JIA entering adulthood with active disease1—and represents a significant medical, financial, and emotional burden for patients, for their families, and for society. In the United States alone, arthritis and rheumatic diseases impact more than 46 million adults and 300,000 children, at a cost of $128 billion annually in direct and indirect medical costs. Multiple studies have shown that adults with JIA have lower rates of employment than matched controls, and health related quality of life is diminished in adults with JIA, particularly in those with active disease.4 Prompt recognition of the disease is important in preventing permanent disability, however, lack of specific confirmatory testing often delays diagnosis. The optimal management of JIA remains complicated and poorly defined, despite recent advances in therapy1; important side effects of many of the newer therapeutic agents are increasingly being recognized, although associated risk factors for the development of these adverse events remain unknown.
The etiology of JIA is largely unknown. To our knowledge, there are no data supporting a major role for environmental exposures;5 this does not preclude a role of the environment in the pathogenesis of JIA, but research to identify environmental risk factors is lacking. On the other hand, a genetic component has been implicated from twin and family studies:6 monozygotic twins have a concordance rate between 25% and 40%; the calculated sibling recurrence risk ratio (λs=15-30) is similar to that calculated for type I diabetes; sibling pairs tend to show concordance for age of onset, subtype and course; and a subset of patients with JIA exhibits a heritable predisposition to develop this disease with an autosomal dominant pattern of inheritance.
Yet, the genetic etiology of JIA remains elusive. JIA is an example of a complex phenotype that is likely to be determined by the net result of interactions between multiple genetic and environmental factors. Previous attempts at identifying the genetic basis of this disease through candidate gene studies have met with limited success. The major histocompatibility complex (MHC), in particular, the HLA-DRB1 locus, has been established as having the strongest influence on susceptibility to JIA,7 contributing ˜20% of the proportion of sibling recurrent risk.8 Non-MHC loci are important as well, although candidate gene studies have only convincingly demonstrated associations for a few loci, and only four (PTPN22, STAT4, IL2-IL21, and IL2RA) have shown association in the same direction in two or more studies.6,9-11 An inherent problem with candidate gene association studies is their reliance on a suspected disease-causing gene(s), whose identification derives from a particular biological hypothesis regarding pathogenesis of the disease or from previous work with related diseases. Since the pathophysiological mechanisms underlying JIA are unknown, continued use of the hypothesis-driven candidate gene association approach is likely to miss many important genetic risk factors for the disease. In view of all the foregoing it is clear a need exists to further characterize and elucidate the genetic and molecular mechanisms underlying this devastating disease.